Virus contamination poses a threat to the safety of biopharmaceuticals derived from recombinant or human plasma sources. Manufacturing processes must provide clearance of endogenous and adventitious viruses to ensure product safety. To that end, filters have been developed that provide virus removal. To be commercially effective and cost-efficient, such filters must provide effective virus removal while maximizing product recovery, and must be reliable, consistent and capable of validation.
Virus removal from liquid streams, particularly process streams in the biotech and pharmaceutical industry, has been practiced for some time. High viral clearance, high product flux, very high protein passage and simplicity of operation are the goals of the end-user, yet the prior art does not provide a solution that satisfies all of these goals. Since high viral clearance is always needed, it is the other process goals that have suffered. Meeting these other goals would substantially increase production efficiency and thus lower processing cost.
The prior art provides several membrane types and filtration modes for viral clearance. One such product is the Viresolve NFR filters with Retropore® membrane that is used to remove retroviruses from recombinant protein solutions or human plasma sources. U.S. Pat. No. 7,108,791 B2 discloses a virus removal methodology using Viresolve NFR filters, suitable for conducting a high-flux fluid separation of virus from a protein in the course of biopharmaceutical manufacture, the methodology comprising the steps of: (a) providing a filtration device comprising a housing having a fluid inlet and a filtrate outlet, and containing at least two interfacially contiguous asymmetric membranes, wherein: (i) the asymmetric membranes are each substantially hydrophilic, (ii) at least two of the hydrophilic membranes are each capable of substantially selectively preventing the passage therethrough of said virus and substantially permitting the passage therethrough of said protein, (iii) at least two of the asymmetric membranes have each a tight-side and open-side, (iv) the foremost asymmetric membrane is oriented such that fluid introduced in said housing through the fluid inlet commences passage through said foremost asymmetric membrane through its open side. It also claims that each of said asymmetric membranes are substantially identical in their composition and porosity, and wherein the porosity of each said asymmetric membranes is defined to enable performance of the virus removal methodology, yielding a log reduction value (LRV) greater than 6 and a protein passage greater than 98%.
Consistency in device-to-device performance is critically important for users of membrane filtration devices in order to predict filtration performance from run to run, and to scale-up or otherwise engineer and design processes. Users often cite performance consistency as one of the most important factors in filter selection. In the case of bacterial or virus filtration, the performance criteria important to users include throughput capacity, flux (or permeability), and retention of bacteria or viruses.
Capacity is important in high value filtration processes such as virus removal in biopharmaceutical manufacturing. Capacity relates to the length of time, or volume of fluid that can be filtered before the filtration rate is reduced through plugging by retained species or fouling, etc., to an uneconomic level. High capacity filtration improves process economics by reducing processing time and the amount of filter area required. High flux becomes critical in medium- and large-scale manufacturing operations where process equipment is required to be turned around rapidly to process the next batch of product. In all these operations, repeatability of filter performance from batch to batch is very important.
Performance variability may depend on a number of factors such as membrane variability, lot-to-lot protein variability, variability in operating parameters, etc. Manufacturers of the therapeutic proteins take measures to minimize lot-to-lot protein variability. Membrane variability can be defined by the difference of properties from manufacturing lot to lot. A manufacturing lot, or batch, the terms are interchangeable, is defined by the manufacturer. A lot can be the production output from a single polymer solution volume in immersion casting, or the output from an operating shift. It is common in flat sheet membrane to label each manufactured roll as a lot or sub-lot. A single roll or lot may also be subdivided based on the variability within that roll. There are many factors that influence membrane performance, including the pore size distribution, the membrane chemistry, membrane thickness, membrane porosity, and others. While membrane manufacturing processes are designed to control all of these factors to maximize uniformity and consistency, there will inevitably be some distribution within normal manufacturing conditions for all of these variables. This membrane variability contributes to device-to-device performance consistency. Methods used to reduce variability in a device through selective layering is described herein.
In addition to reducing device variability, membrane device manufacturers desire to optimize and/or maximize device properties of a population of devices. As will be described, embodiments herein provide for methods to increase the average capacity (defined below) of a population of manufactured devices through selective layering as compared to a population manufactured by standard non-selective layering.
The ability to control device consistency is particularly important for multilayered filtration devices. For these devices, not only is the variability of the membrane important, but membrane variability can affect the interaction between the layers, as will be shown below.
It therefore would be desirable to provide a multi-layer membrane device with reduced performance variability, as well as a method of reducing the performance variability of such devices, notwithstanding the inherent variability of the membrane manufacturing process.